General Background
A wide variety of cytotoxic agents or therapy, such as chemotherapy, immunosuppressive agents, biologics, radiotherapy and combined therapy thereof, are used in the treatment of cancer and many other diseases. However, when cancer cells are killed, normal cells are also damaged simultaneously when the treatment is used on human body. Typically, a series of toxic side effects occur, for example, the damage on important tissues and/or organs, such as heart, liver, kidney, lung, bone marrow, etc.
Radiation pneumonitis frequently appears after irradiation of the lung area during the treatment of lung cancer, breast cancer, and esophageal cancer. Radiation pneumonitis can lead to life threatening fibrotic lesion in the lung. Usually, the severity of pulmonary fibrosis is correlated with irradiation dosage. In addition, abdominal irradiation may induce hepatitis, enteritis, necrosis and fibrosis; whereas cavitas pelvis irradiation may induce rectitis and cystitis, of which the resulted mild symptom is mucosal dropsy and in the severe case is fibrosis.
The manifestations of pulmonary toxicity caused by drugs used in chemotherapy are interstitial pneumonia and pulmonary fibrosis. Drugs like Bleomycin, BCNU, MTX, Mitomycin, should be withdrawn once pulmonary toxicity appears, followed by further treatment with hormone, antibiotic, vitamin, etc. Drugs inducing liver toxicity include BCNU, CCNU, Ara-C, L-ASP, VP-16, 6-MP, high dose of MTX, CTX, DDP, DNR, Act-D, STZ, VCR, etc. Liver toxicity is divided into three types: (1) hepatocyte function defect and chemical hepatitis; (2) venous occlusion diseases; and (3) chronic liver fibrosis.
Drugs used in chemotherapy also cause renal toxicity. Most cytotoxic drugs, such as DDP, MTH, STZ, IFO, high dose of MTX, cause renal functional defect by damaging renal glomerulus, rather than renal tubule. Renal toxicity may occur immediately after drug administration or develops subsequently, after long-term medicine treatment or after withdrawal of the drugs.
Toxicity induced by combined chemotherapy and radiotherapy is divided into early stage and late stage, of which the late stage mainly involves damages of connective tissue within heart, kidney, lung, etc. Interstitial cardiac fibrosis may occur after three months following radiotherapy. For example, combined therapy of adriamycin and radiotherapy may increase associated cardiac toxicity. Drugs used in chemotherapy, such as bleomycin, adriamycin and mitomycin, may increase the incidence rate and severity of radiation pneumonitis and pulmonary fibrosis.
Injury of Organs Induced by Radiation
Radiotherapy is a common means for the treatment of malignant tumors. Radiation on pulmonary carcinoma, mammary adenocarcinoma, esophageal carcinoma, malignant lymphoma, or other thoracic malignant tumors will also damage normal pulmonary tissue in the irradiation filed, resulting in inflammation, which is termed as radiation-induced lung injuries, i.e. acute radiation pneumonitis.
Radiation pneumonitis is a major detrimental side effect during radiotherapy, including early change (radiation pneumonitis) and advanced change (radiation fibrosis). Everyone who has undergone a pulmonary irradiation will have such change. In most cases, such change is asymptomatic, but a change accompanied by infection will produce symptoms, which is called acute radiation pneumonitis. Asymptomatic inflammation will be gradually absorbed and disappear to form various degrees of pulmonary parenchyma fibrosis after completion of irradiation. Pulmonary fibrosis occurs within about 6 months after irradiation, and then gradually deteriorates to be worst within 1 year. Pathological changes of the acute phase of radiation pneumonitis occur mostly within 1 to 2 months after irradiation, but in some cases they are observed after a half year post radiotherapy. They manifest themselves as congestion, edema and cellular infiltration due to damage of pulmonary vessels (especially capillary vessel), decreased reproduction of type II alveolar cells, lymphangiectasis, and formation of hyaline membrane. The acute changes may spontaneously disappear, but they generally cause desmoplasia, fibrosis, and hyalinization of the lung. The chronic phase generally occurs after 9 months of irradiation, the pathologic of which is extensive fibrosis of pulmonary alveolus, contraction of lung, inner membrane thickening, stiffing, narrowing or obstruction of the lumen of blood capillary resulting in increased resistance force of pulmonary circulation and pulmonary artery hypertension. Pleura can also thicken as the result of inflammation and fibrosis. Epithelial anaplasia of the bronchiolar mucous lining and secondary pulmonary infection can promote radiation fibrosis.
Development of radiation pneumonitis is mostly correlate with the irradiation volume, while the other factors, such as dosage and separation, conditions of the individual, individual differences, and the presence of chronic lung diseases can also contribute. Use of anti-cancer agents, such as ADM, PYM, and VCR concurrently with radiation, as well as smoking, will also promote development of radiation pneumonitis.
The severity of lung injuries is closely correlated with the area of the lung irradiated, and the dose and rate of exposure. The pathological changes are exudative inflammation of the acute phase and, extensive pulmonary fibrosis of the chronic phase. The larger the dose received (more than 20 Gy), the more severe the radiation pneumonitis, eventually leading to the extensive pulmonary fibrosis. The occurrence of radiation pneumonitis greatly hampers the treatment of thoracic malignancies which are clinically common and progress rapidly, and thus negatively impacts patients' quality of life, or even threatens their lives. The incidence of radiation pneumonitis reportedly varies, generally in the range of about 8.25% to 58%.
Currently, there are not clinically available medicaments specifically for radiation-induced lung injuries. The common treatments include: i) corticoid therapy, to control inflammation; ii) anticoagulant therapy, to prevent small vascular embolism; iii) high concentration oxygen therapy, to alleviate hyoxemia; and iv) antibiotic therapy, to prevent secondary infection. The principle of administration is: i) prednisone or dexamethasone orally administered for general patients of radiation pneumonitis; ii) dexamethasone administered by intravenous infusion for severe patients; iii) antibiotics concurrently administered for patients who have concomitant pulmonary infection. However, the effect of hormone treatment is still in question, because some investigations have showed that hormone treatment has no effect on radiation-induced lung injuries.
It is undoubted that radiotherapy plays an important role in the treatment of malignancies, however, its side effects of irradiative responses and injuries are also noteworthy. High dose of irradiation damages tumor cells as well as normal cells, causing detrimental responses in the patients. If the irradiation dose is not limited, it will kill normal cells when it kills the tumor. Therefore, radiation therapy can only kill tumor cells to the most extent where it is tolerated by normal tissues. In the situation of a radio-sensitive tumor, a tumor-killing dose will not damage normal tissues around the tumor, and hence the radiation therapy can cure the tumor. While for a tumor whose fatal irradiation dose can also kill or damage the surrounding normal tissue, normal tissue will be greatly damaged at the same time with tumor cells. Therefore, it is necessary to utilize suitable treatment modalities to increase the ratio of the doses received by tumor versus normal tissue so as to cure the tumor but not overly influence the normal tissue. In addition, there is an earnest need in the art to develop a method with increased irradiation dose and decreased radiation-induced injuries.
In summary, cytotoxic therapy such as chemotherapy and radiotherapy often causes acute tissue injury and fibrosis, thus limiting the efficacy and safety of the treatment. Currently there is no effective prophylactic or treatment regimen available for such side effects during the treatment using a cytotoxic therapy.